Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung

G McLachlan; H Davidson; E Holder; L A Davies; I A Pringle; S G Sumner-Jones; A Baker; P Tennant; C Gordon; C Vrettou; R Blundell; L Hyndman; B Stevenson; A Wilson; A Doherty; D J Shaw; R L Coles; H Painter; S H Cheng; R K Scheule; J C Davies; J A Innes; S C Hyde; U Griesenbach; E W F W Alton; A C Boyd; D J Porteous; D R Gill; D D S Collie

doi:10.1038/gt.2011.55

Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung

G McLachlan, H Davidson, E Holder, L A Davies, I A Pringle, S G Sumner-Jones, A Baker, P Tennant, C Gordon, C Vrettou, R Blundell, L Hyndman, B Stevenson, A Wilson, A Doherty, D J Shaw, R L Coles, H Painter, S H Cheng, R K ScheuleJ C Davies, J A Innes, S C Hyde, U Griesenbach, E W F W Alton, A C Boyd, D J Porteous, D R Gill, D D S Collie

Research output: Contribution to journal › Article › peer-review

Abstract

We use both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy. Here, we report the use of a large animal model to assess three non-viral GTAs: 25 kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle formulated with polyethylene glycol-substituted lysine 30-mer. GTAs complexed with plasmids expressing human cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA were administered to the sheep lung (n=8 per group) by aerosol. All GTAs gave evidence of gene transfer and expression 1 day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (two out of eight) and PEI (one out of eight). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion was that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.

Original language	English
Pages (from-to)	996-1005
Number of pages	10
Journal	Gene Therapy
Volume	18
Issue number	10
DOIs	https://doi.org/10.1038/gt.2011.55
Publication status	Published - 2011

Keywords / Materials (for Non-textual outputs)

gene delivery
LUNG
non-viral
Sheep
Cystic Fibrosis
AEROSOL

Access to Document

10.1038/gt.2011.55

http://www.nature.com/gt/journal/v18/n10/full/gt201155a.html

Cite this

McLachlan, G., Davidson, H., Holder, E., Davies, L. A., Pringle, I. A., Sumner-Jones, S. G., Baker, A., Tennant, P., Gordon, C., Vrettou, C., Blundell, R., Hyndman, L., Stevenson, B., Wilson, A., Doherty, A., Shaw, D. J., Coles, R. L., Painter, H., Cheng, S. H., ... Collie, D. D. S. (2011). Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung. Gene Therapy, 18(10), 996-1005. https://doi.org/10.1038/gt.2011.55

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title = "Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung",

abstract = "We use both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy. Here, we report the use of a large animal model to assess three non-viral GTAs: 25 kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle formulated with polyethylene glycol-substituted lysine 30-mer. GTAs complexed with plasmids expressing human cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA were administered to the sheep lung (n=8 per group) by aerosol. All GTAs gave evidence of gene transfer and expression 1 day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10\% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (two out of eight) and PEI (one out of eight). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion was that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.",

keywords = "gene delivery, LUNG, non-viral, Sheep, Cystic Fibrosis, AEROSOL",

author = "G McLachlan and H Davidson and E Holder and Davies, \{L A\} and Pringle, \{I A\} and Sumner-Jones, \{S G\} and A Baker and P Tennant and C Gordon and C Vrettou and R Blundell and L Hyndman and B Stevenson and A Wilson and A Doherty and Shaw, \{D J\} and Coles, \{R L\} and H Painter and Cheng, \{S H\} and Scheule, \{R K\} and Davies, \{J C\} and Innes, \{J A\} and Hyde, \{S C\} and U Griesenbach and Alton, \{E W F W\} and Boyd, \{A C\} and Porteous, \{D J\} and Gill, \{D R\} and Collie, \{D D S\}",

year = "2011",

doi = "10.1038/gt.2011.55",

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McLachlan, G, Davidson, H, Holder, E, Davies, LA, Pringle, IA, Sumner-Jones, SG, Baker, A, Tennant, P, Gordon, C, Vrettou, C, Blundell, R, Hyndman, L, Stevenson, B, Wilson, A, Doherty, A , Shaw, DJ, Coles, RL, Painter, H, Cheng, SH, Scheule, RK, Davies, JC, Innes, JA, Hyde, SC, Griesenbach, U, Alton, EWFW, Boyd, AC, Porteous, DJ, Gill, DR & Collie, DDS 2011, 'Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung', Gene Therapy, vol. 18, no. 10, pp. 996-1005. https://doi.org/10.1038/gt.2011.55

TY - JOUR

T1 - Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung

AU - McLachlan, G

AU - Davidson, H

AU - Holder, E

AU - Davies, L A

AU - Pringle, I A

AU - Sumner-Jones, S G

AU - Baker, A

AU - Tennant, P

AU - Gordon, C

AU - Vrettou, C

AU - Blundell, R

AU - Hyndman, L

AU - Stevenson, B

AU - Wilson, A

AU - Doherty, A

AU - Shaw, D J

AU - Coles, R L

AU - Painter, H

AU - Cheng, S H

AU - Scheule, R K

AU - Davies, J C

AU - Innes, J A

AU - Hyde, S C

AU - Griesenbach, U

AU - Alton, E W F W

AU - Boyd, A C

AU - Porteous, D J

AU - Gill, D R

AU - Collie, D D S

PY - 2011

Y1 - 2011

N2 - We use both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy. Here, we report the use of a large animal model to assess three non-viral GTAs: 25 kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle formulated with polyethylene glycol-substituted lysine 30-mer. GTAs complexed with plasmids expressing human cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA were administered to the sheep lung (n=8 per group) by aerosol. All GTAs gave evidence of gene transfer and expression 1 day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (two out of eight) and PEI (one out of eight). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion was that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.

AB - We use both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy. Here, we report the use of a large animal model to assess three non-viral GTAs: 25 kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle formulated with polyethylene glycol-substituted lysine 30-mer. GTAs complexed with plasmids expressing human cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA were administered to the sheep lung (n=8 per group) by aerosol. All GTAs gave evidence of gene transfer and expression 1 day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (two out of eight) and PEI (one out of eight). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion was that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.

KW - gene delivery

KW - LUNG

KW - non-viral

KW - Sheep

KW - Cystic Fibrosis

KW - AEROSOL

UR - https://www.scopus.com/pages/publications/80054087238

U2 - 10.1038/gt.2011.55

DO - 10.1038/gt.2011.55

M3 - Article

C2 - 21512505

SN - 1476-5462

VL - 18

SP - 996

EP - 1005

JO - Gene Therapy

JF - Gene Therapy

IS - 10

ER -

Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Other files and links

Fingerprint

Validation of recombinant Sendai virus in a non-natural host model

University of Glasgow Seminar: Gene Therapy for CF - Time to Deliver.

17th Annual Meeting of the American Society of Gene and Cell Therapy

Optimising delivery and analysis of gene transfer in the sheep lung

Cite this

Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Other files and links

Fingerprint

Research output

Validation of recombinant Sendai virus in a non-natural host model

Activities

University of Glasgow Seminar: Gene Therapy for CF - Time to Deliver.

17th Annual Meeting of the American Society of Gene and Cell Therapy

Optimising delivery and analysis of gene transfer in the sheep lung

Cite this